This project involves the conduct of therapeutic clinical trials for treatment of chronic graft versus host disease (cGVHD) following allogeneic transplantation. The ultimate goal is to make transplant a safer alternative treatment modality for patients with severe inherited immune deficiencies. However, in the context of these studies of the pathophysiology and treatment of cGVHD the clinical trial of photopheresis is open to all patients post allogeneic transplant. Specifically, we are conducting a clinical trial to examine the potential of extracorporeal photophoresis to treat chronic graft versus host disease and to understand how this modality works immunologically. If graft versus host disease risks can be reduced it would then reduce one of the risks of allogeneic transplantation for inherited primary immune deficiencies. In order to reduce graft versus host disease we have begun a clinical trial to study the effect of extracorporeal photopheresis (ECP) on cGVHD. We found novel immunologic changes in ratios of central and effector memory T-cells that correct following three months of ECP. Chronic graft versus host disease (cGvHD) remains a problematic complication of allogeneic hematopoietic stem cell transplantation. Laboratory parameters correlated with cGvHD have not been fully defined, though changes in CD4/CD8 ratios occur and a decrease in CD4+ central memory T-cells has been noted. Extracorporeal photopheresis (ECP) is an effective therapy for steroid-refractory cGvHD. In collaboration with others at NIH we have noted specific types of skin and facia changes in chronic graft versus host disease and developed methods of evaluation in close collaboration with our colleagues in Dermatology here at NIH. We have noted changes in lymphocyte subsets following ECP. CD4+ and CD8+ T-cell central and effector memory populations were enumerated by flow cytometry in a cohort of 37 patients post-allogeneic transplantation with symptomatic cGvHD. 7 of the patients with symptomatic cGvHD were treated with ECP over 6 months and prospectively assessed for changes in lymphocyte subsets. There was a highly significant correlation of an increase in CD8+ central memory cells and a concomitant decrease in CD4+ central memory cells. These data indicate a high correlation between disturbances in the balance of central and effector memory populations and cGvHD suggesting utility in following responses to therpy. More recently we have developed mouse models of chronic GVHD and shown that adenosine A2a specific agonists can prevent development of GVHD or reverse GVHD in this mouse model.